Circadian disruption induces sex-specific Alzheimer's pathophysiology and immune cell reprogramming

Circadian disruption (CD) is increasingly recognized as a sex-specific risk factor for Alzheimers disease (AD). However, the mechanisms linking CD to AD, and the role of biological sex in this interaction, are unclear. Immunometabolic regulation is extensively circadianly timed, has sex-specific phenotypes, and plays a role in AD. Therefore, we hypothesized that CD affects the timing of immunometabolism, contributing to the sex-specific effects of CD on AD. To demonstrate this, we subjected male and female APP/PS1 mice to chronic disruptive lighting to model circadian disruption, finding CD induced a female-specific reduction in amyloid plaque burden but an increase in the infiltration of peripheral macrophages into the brain. Concomitantly, we found macrophages exhibited CD-associated immune reprogramming, which in females led to altered immunometabolic timing, an increase of macrophages in the activated state, and elevated levels of reactive oxygen species (ROS), supporting a role for immunometabolism in the sex-specific effects of CD in AD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/721994v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@b9a59forg.highwire.dtl.DTLVardef@289219org.highwire.dtl.DTLVardef@18fe804org.highwire.dtl.DTLVardef@c96bb8_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LICircadian disruption reduces A{beta} plaque load specifically in female mice C_LIO_LIPeripheral immune infiltration correlates with reduced A{beta} plaques in females C_LIO_LICircadian disruption coordinates phasing of circadian immunometabolic proteins C_LIO_LIIn females, circadian phase advancement correlates with increased ROS C_LI